Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population

Chikashi Terao, Hajime Yoshifuji, Akinori Kimura, Takayoshi Matsumura, Koichiro Ohmura, Meiko Takahashi, Masakazu Shimizu, Takahisa Kawaguchi, Zhiyong Chen, Taeko K. Naruse, Aiko Sato-Otsubo, Yusuke Ebana, Yasuhiro Maejima, Hideyuki Kinoshita, Kosaku Murakami, Daisuke Kawabata, Yoko Wada, Ichiei Narita, Junichi Tazaki, Yasushi KawaguchiHisashi Yamanaka, Kimiko Yurugi, Yasuo Miura, Taira Maekawa, Seishi Ogawa, Issei Komuro, Ryozo Nagai, Ryo Yamada, Yasuharu Tabara, Mitsuaki Isobe, Tsuneyo Mimori, Fumihiko Matsuda

研究成果: ジャーナルへの寄稿学術論文査読

129 被引用数 (Scopus)

抄録

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10-13, OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10-7, OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10-21, OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B*52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.

本文言語英語
ページ(範囲)289-297
ページ数9
ジャーナルAmerican Journal of Human Genetics
93
2
DOI
出版ステータス出版済み - 08-08-2013
外部発表はい

All Science Journal Classification (ASJC) codes

  • 遺伝学
  • 遺伝学(臨床)

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